The long-term objectives of this research program are (1) to achieve efficient total syntheses of natural products, which could benefit human health, through the development of powerful chemical methods and strategies, and (2) to investigate the modes of action of bioactive natural products. This grant application addresses the chemical problems posed by five biologically active natural products and its Specific Aims are: (1) to develop novel synthetic routes to the natural products harziphilone and fleephilone and characterize how these compounds inhibit binding between the HIV-1 Rev protein and the Rev Responsive Element (RRE) of viral mRNA, a required event in the replication of HIV-1 ; and (2) to achieve concise syntheses of TAEMC-161 and the steroidal antibiotics viridiol and viridin. The function of the protein HIV-1 Rev is essential for the replication of HIV and, therefore, an excellent target for therapeutic intervention. Harziphilone and fleephilone are natural products that block the critical HIV-1 Rev/RRE RNA interaction. The important bioactivities and unique structural features of these compounds make them compelling objectives for organic synthesis. A tandem process comprising three structural transformations is proposed to convert an acyclic bis-ynone to harziphilone, while an aza-ring annulation featuring the intramolecular addition of a carbon nucleophile to pyridinium or iminium ions is the cornerstone of the proposed approach to the unusual structure of fleephilone. The furanosteroid viridin and its structural relatives are cell permeable, selective inhibitors of PI 3-kinase, an enzyme essential for many biological processes, and have potential as therapeutic agents for the treatment of neoplasms in humans. As such, these compounds and other natural products that act by analogous mechanisms are prime targets for organic synthesis. This grant application describes how an efficient reaction sequence featuring metal-catalyzed cyclotrimerization, carbonyl addition, and sequential electrocyclic reactions can be integrated into a general plan for syntheses of viridiol and viridin and also illustrates a structural and potential chemical relationship between these compounds and the recently described natural product TAEMC-161. [unreadable] [unreadable]